The present invention relates to a method for the treatment of arterial stenosis and, more particularly, to a method of inhibiting intimal hyperplasia following balloon angioplasty by treatment with zaprinast.
(NOTE: Literature references on the following background information and on the conventional test methods and laboratory procedures well known to the person skilled in the art and other such state-of-the-art techniques as used herein are indicated in parentheses and appended at the end of the specification.)
Balloon angioplasty is a widely used medical procedure with an initial success rate of greater than ninety percent (26). Success is defined as a reduction of the original stenosis by more than fifty percent. However, arterial restenosis is a significant complication and occurs in approximately 17-40% of all patients (1-5). Mechanisms contributing to vascular restenosis include platelet aggregation (27), local vasoconstriction (28), and intimal proliferation of smooth muscle cells. Treatment with anticoagulants (29), smooth muscle vasodilators (30), and antiproliferative agents (31) have not successfully inhibited clinical restenosis. Recently, it has been suggested that activation of the vascular renin angiotensin system (RAS) in diseased vessels stimulates intimal smooth muscle hyperplasia (32). Human trials evaluating angiotensin converting enzyme inhibitors for arterial restenosis have not been successful (33), but further trials are ongoing.
Intimal hyperplasia has been described in part as an uncontrolled growth response of vascular smooth muscle cells (VSMCs) following vascular reconstructions (e.g. balloon angioplasty and bypass grafting) and is a leading cause of surgical reintervention for restenosis (1-5). Although there is no available therapy to prevent the formation of intimal hyperplasia, recent advancements were made by McNamara and colleagues (6). They demonstrated that the intimal proliferative response was inhibited by altering the level of the naturally occurring metabolite nitric oxide (NO) with L-arginine administration in animal models of balloon angioplasty. Their hypothesis was that NO, formed by the vascular endothelium, would inhibit intimal hyperplasia similar to its ability to inhibit VSMC proliferation in vitro (7-9). In addition, Furuya and colleagues (10) recently showed that administering C-type natriuretic peptide (CNP) also attenuated intimal thickening after vascular injury in rats.
CNP is a member of the natriuretic family of peptides which also includes atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). CNP is synthesized in the vascular endothelial cell (11,12), and its receptor, guanylyl cyclase type B (GC-B), is expressed in the vascular smooth muscle cell (13,14). Quiescent smooth muscle cells express minimal amounts of GC-B; however, during growth and replication GC-B expression is dramatically increased both in vitro (13,14) and in vivo (10). CNP, like NO, increases intracellular cGMP upon receptor activation, and potently inhibits cellular proliferation and DNA synthesis in cultured rat VSMCs (15,16). However, since some of the biologies of NO and the natriuretic peptides have been attributed to non-cGMP mediated mechanisms (17), the present inventor sought to evaluate the role of cellular CGMP in the proliferative and growth response of VSMCs. One means to increase cellular CGMP levels is to inhibit its degradation to its 5'-monophosphate. Cyclic-AMP and cGMP are metabolized by cellular phosphodiesterase enzymes. Currently, five specific classes of enzymes have been defined. The type five enzyme is a cGMP specific phosphodiesterase designated as PDE-V.